Costimulatory receptor mechanisms

In addition to receiving antigen-driven signals through their T cell receptors (TCRs), CD4+ T cells also require activation of the costimulatory receptor CD28 to ensure full activation. Rodríguez-Jorge et al. combined mathematical modeling of signaling by the TCR and by the pattern recognition receptor Toll-like receptor (TLR5) to predict how the two pathways could combine to induce T cell activation. Experiments then showed how the TCR and TLR5 pathways converged on the activation of critical transcriptional regulators needed for T cell activation, suggesting that TLR5 plays a role similar to that of CD28 in T cell activation.

Abstract

CD4+ T cells recognize antigens through their T cell receptors (TCRs); however, additional signals involving costimulatory receptors, for example, CD28, are required for proper T cell activation. Alternative costimulatory receptors have been proposed, including members of the Toll-like receptor (TLR) family, such as TLR5 and TLR2. To understand the molecular mechanism underlying a potential costimulatory role for TLR5, we generated detailed molecular maps and logical models for the TCR and TLR5 signaling pathways and a merged model for cross-interactions between the two pathways. Furthermore, we validated the resulting model by analyzing how T cells responded to the activation of these pathways alone or in combination, in terms of the activation of the transcriptional regulators CREB, AP-1 (c-Jun), and NF-κB (p65). Our merged model accurately predicted the experimental results, showing that the activation of TLR5 can play a similar role to that of CD28 activation with respect to AP-1, CREB, and NF-κB activation, thereby providing insights regarding the cross-regulation of these pathways in CD4+ T cells.